Clinical characteristics.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.

Diagnosis/testing.

The diagnosis of USH1 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of six genes – MYO7A, USH1C, CDH23, PCDH15, USH1G, and CIB2 – establishes the diagnosis if clinical features are inconclusive. Possible digenic inheritance has been reported in a few families.

Management.

Treatment of manifestations: In infants: an initial trial of hearing aids to stimulate residual hearing and accustom the infant to auditory stimulation. Cochlear implantation should be considered as young as medically feasible. Sign language and tactile signs (once visual loss occurs) for families who choose non-auditory communication. Specialized training from educators of the hearing impaired. Vestibular compensation therapy for children with residual balance function and sensory substitution therapy for individuals with complete absence of vestibular function. Standard treatments for retinitis pigmentosa.

Surveillance: Annual audiometry and tympanometry in those with cochlear implant or hearing aids to assure adequate auditory stimulation. Annual otoscopic exam with tympanometry in children with profound loss to evaluate for chronic otitis media. Annual ophthalmologic evaluation, fundus photography, visual acuity, visual field testing, electroretinography, optical coherence tomography, and fundus autofluorescence from age 20 years.

Agents/circumstances to avoid: Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution. Progressive loss of peripheral vision impairs the ability to safely drive a car.

Evaluation of relatives at risk: The hearing of at-risk sibs should be assessed as soon after birth as possible to allow early diagnosis and treatment of hearing loss.

Genetic counseling.

USH1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the USH1-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Usher syndrome type I (USH1) should be suspected in individuals with:

• Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see Hereditary Hearing Loss and Deafness Overview);
• No significant or delayed vestibular responses;
• Retinitis pigmentosa (RP);
• Normal general health and intellect and otherwise normal physical examination;
• A family history consistent with autosomal recessive inheritance.

Establishing the Diagnosis

The diagnosis of USH1 is established in a proband with the above clinical features and family history. Identification of biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1 establishes the diagnosis if clinical features are inconclusive.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

The phenotype of USH1 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP; therefore, the recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing is rarely useful and typically NOT recommended.

An Usher syndrome multigene panel or a more comprehensive multigene panel (e.g., inherited retinal dystrophy panel, hereditary hearing loss panel) that includes the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Hearing loss. The hearing loss in Usher syndrome type I (USH1) is congenital (i.e., present at birth), bilateral, severe-to-profound sensorineural hearing impairment (SNHI). While congenital SNHI should be identified through universal hearing screening at birth, occasionally false negative screening or missed screening before discharge to home results in delayed diagnosis until speech delay is obvious. Affected individuals do not develop speech unless fitted with cochlear implants. Hearing aids are usually inadequate in individuals with USH1 because of the severity of the hearing loss. Alternatively, sign language and tactile signs (once visual loss occurs) are communication options for families who choose nonauditory communication.

Imbalance. The imbalance in individuals with USH1 is associated with the deafness and is a defining feature of this disorder. While the timing and extent of "vestibular areflexia" is not fully understood, children with USH1 typically walk later than usual, at approximately age 18 months to two years. Older children may seem "clumsy" and experience frequent accidental injuries or have difficulty with activities requiring balance, such as riding a bicycle or playing sports.

Visual loss. Children with USH1 are often misdiagnosed as having nonsyndromic hearing impairment until delayed walking or tunnel vision and night blindness – early signs of retinitis pigmentosa (RP) – become severe enough to be noticeable, either by parents and teachers or by the individual. The onset of RP in individuals with USH1 is variable but can start in early infancy or childhood. RP is progressive, bilateral, symmetric photoreceptor degeneration of the retina that initiates in the midperiphery; rods (photoreceptors active in the dark-adapted state) are mainly affected first, causing night blindness and constricted visual fields (tunnel vision). Cones (photoreceptors active in the light-adapted state) are affected second and eventually die, resulting in central blindness. Contrast sensitivities, color vision, and mobility may become severely affected as the retinal degeneration progresses.

Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH1 age 30-40 years. Visual impairment worsens significantly each year [Pennings et al 2004]. Individuals with USH1 may become completely blind. Cataracts and/or cystoid macular edema sometimes reduce central vision. These two associated conditions are treatable.

Heterozygotes. Heterozygotes are asymptomatic.

Genotype-Phenotype Correlations

A genotype-phenotype correlation has been reported for pathogenic variants in the genes associated with USH1. Homozygous null (e.g., nonsense, frameshift, splicing) variants are associated with USH1, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic hearing impairment or atypical Usher syndrome. This genotype-phenotype correlation suggests that deaf children found to be homozygous for hypomorphic variants in an USH1 gene are unlikely to develop vision loss.

USH1C

• c.1220delG. Audiometric screening of ten individuals of Yemenite Jewish ancestry revealed that individuals younger than age 40 years had normal hearing while older individuals showed mild-to-severe high-frequency hearing loss. This is the first report of individuals with USH1 and adult-onset hearing loss rather than congenital hearing loss [Khateb et al 2012].
• c.667G>T (p.Gly223Cys). Heterozygous variant reported in individuals with autosomal dominant nonsyndromic hearing impairment from a Korean cohort [Song et al 2020]

CDH23. A reduced frequency of null (e.g., nonsense, frameshift, splice) variants in CDH23 was observed in individuals with less severe phenotypes, with approximately 88%, 67%, and 0% of null variants found in persons with typical Usher type I (USH1D), atypical Usher syndrome, and nonsyndromic deafness type 12 (DFNB12), respectively [Bolz et al 2001, Bork et al 2001, Liu et al 2001, Astuto et al 2002, Bork et al 2002, Valero et al 2019].

PCDH15. Hypomorphic variants were associated with nonsyndromic hearing impairment indicating that residual function with some missense variants are sufficient for normal vision but not hearing, while more severe pathogenic variants result in USH1 [Ahmed et al 2001, Alagramam et al 2001, Ahmed et al 2003, Doucette et al 2009].

CIB2. To date all known pathogenic variants (copy number variants, splicing, indels, and missense) identified in CIB2 are associated with DFNB48, except one variant, c.192G>C (p.Glu64Asp), identified in four individuals from a single consanguineous Pakistani family with USH1J [Riazuddin et al 2012]. Booth et al [2018], however, reported three different loss-of-function variants in three families from diverse origins that cause DFNB48 (autosomal recessive nonsyndromic hearing loss) and not USH1.

Penetrance

Penetrance is complete in Usher syndrome type I.

Nomenclature

The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, presence or absence of vestibular areflexia, and age at onset of retinitis pigmentosa). The letters (e.g., USH1C, USH1B) indicate the molecular subtype with biallelic pathogenic variants in one of the related genes listed in Table 1.

Note: Gerber et al [2006] provide evidence that the USH1A locus does not exist; six of the nine families from the Bressuire region of France originally reported to map to this locus have been found to have pathogenic variants in MYO7A (USH1B).

Prevalence

In older publications the prevalence of Usher syndrome has been reported to range from 3.2 to 6.2 per 100,000. Usher syndrome was estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. Many of these estimates were made prior to 1989, when Möller et al [1989] subdivided Usher syndrome into Usher syndromes type I and II, and before the recognition of Usher syndrome type III. The specialized educational requirements of the congenitally deaf have historically rendered the population with Usher syndrome type I more accessible for study by researchers. Persons with Usher syndrome type II or Usher syndrome type III, who communicate orally and who are mainstreamed into regular schools, are not well represented in these estimates. It has been argued that the prevalence of Usher syndrome in the general population may therefore be substantially greater than estimated.

A recent study of children with hearing loss in Oregon found pathogenic variants in Usher syndrome-associated genes in 11% and estimated that the prevalence may be as high as one in 6,000 [Kimberling et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type I (USH1), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous.

Persons with USH1 often become disoriented when submerged in water because they lack the sense of where "up" is; they should therefore exercise caution while swimming. Similarly, the vestibular dysfunction increases the risk of falls when walking on sloped or uneven surfaces.

Progressive loss of peripheral vision may eventually impair the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.

Evaluation of Relatives at Risk

It is appropriate to evaluate the hearing of all sibs at risk for USH1 as soon after birth as possible to allow early diagnosis and treatment of hearing impairment.

Additional evaluations include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

UshStat^® gene replacement of MYO7A – A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of UshStat^® in Patients with Usher Syndrome Type 1B. This is an interventional, Phase I/II clinical trial to evaluate the safety and activity of retinal gene therapy to treat RP in individuals with MYO7A-USH1. This trial is active but not recruiting. (See NCT02065011.)

QR-421 antisense treatment – A Study to Evaluate Safety and Tolerability of QR-421a in Subjects with RP Due to Mutations in Exon 13 of the USH2A Gene (Stellar). This is an interventional, Phase I/II clinical trial to evaluate the safety of an antisense oligonucleotide (ASO) therapy to treat RP in individuals with USH2 due to specific USH2A pathogenic variants. (See NCT03780257.)

C-18-04 antioxidant treatment – Safety and Efficacy of NPI-001 Tablets versus Placebo for Treatment of Retinitis Pigmentosa Associated with Usher Syndrome. This is an interventional, two-year, Phase I/II clinical trial to evaluate the safety and efficacy of NPI-001 tablets in individuals with RP associated with Usher syndrome. This trial is active and recruiting. (See NCT04355689.)

CL-17-01 antioxidant treatment – A Phase I, Single- and Multiple-Ascending Dose Study of the Safety and Tolerability of NPI-001 Solution in Healthy Subjects. This clinical trial established that NPI-001 was generally well tolerated in all but the highest dose and determined key pharmacokinetic parameters of the NPI-001 solution. (See ACTRN12617000911392.)

Search ClinicalTrials.gov in the US, EU Clinical Trials Register in Europe, and ANZCTR in Australia and New Zealand for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamin A supplements. Vitamin A plays an essential role in the visual cycle as the photosensitive intermediate 11 cis retinal. Although treatment with vitamin A palmitate may limit the progression of RP in persons with isolated RP and USH2, no studies have evaluated the effectiveness of vitamin A palmitate in individuals with USH1. Vitamin A is fat soluble and not excreted in the urine. Therefore, high-dose vitamin A dietary supplements should be used only under the direction of a physician because of the need to monitor for harmful side effects such as hepatotoxicity [Sibulesky et al 1999]. Of note, the studies by Berson et al [1993] were performed on individuals older than age 18 years because of the unknown effects of high-dose vitamin A on children. High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (i.e., above the recommended daily allowance for pregnant or lactating women) may be teratogenic to the developing fetus.

Lutein supplements may enhance retinal macular pigment. Lutein, zeaxanthin, meso-zeaxanthin, and their oxidative metabolites accumulate in the human fovea and macula as the macular pigment (MP). They are obtained through dietary sources (green leafy vegetables, yellow and/or orange fruits and vegetables). Inherited retinal dystrophies may cause or be associated with loss of MP [Aleman et al 2001]. Oral administration of lutein (20 mg/day) for seven months had no effect on central vision [Aleman et al 2001]. However, Berson et al [2010] showed that lutein supplementation of 12 mg/day slowed loss of midperipheral visual field among nonsmoking adults with RP taking vitamin A.

Omega 3 supplements (e.g., docosahexaenoic acid [DHA]) may replenish membranes of the photoreceptor outer segments, which are largely composed of polyunsaturated fatty acids. Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity [Hoffman et al 2015].

N-acetyl-cysteine (NAC) supplements. NAC is a safe oral antioxidant used to treat liver toxicity due to acetaminophen overdose. NAC reduces oxidative damage and increases cone function and survival in animal models of RP [Lee et al 2011]. In a Phase l study, 600 mg, 1200 mg, or 1800 mg were safe in individuals with RP and significant improvements were found in cone function, including visual acuity [Campochiaro et al 2020].

Blueberry extract supplements. Blueberries contain anthocyanins, members of the flavonoid group of phytochemicals, which are powerful antioxidants. No studies have been done on individuals with RP or USH1. Because of their natural source, blueberry extract supplements are probably safe and may be efficacious.

Mode of Inheritance

Usher syndrome type I (USH1) is typically inherited in an autosomal recessive manner.

Digenic inheritance and/or disease-modifier genes

• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [Zheng et al 2005, Bonnet et al 2011, Vozzi et al 2011, Yoshimura et al 2014].
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving PDZD7, only two studies have reported evidence of digenic inheritance: Ebermann et al [2010] described an individual with USH2 with heterozygous pathogenic variants in both ADGRV1 and PDZD7; Yoshimura et al [2014] described an individual with USH1 with heterozygous pathogenic variants in both MYO7A and PCDH15. Large meta-analysis of the genetics of Usher syndrome by Jouret et al [2019] concluded that data "do not support the existence of digenic inheritance in Usher syndrome" and suggest that the affected individuals in the above-referenced studies may have had genetic variants undetectable by the genetic testing capabilities available at the time.

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

• The unaffected parents of an individual with USH1 are obligate heterozygotes (i.e., presumed to be carriers of one USH1-causing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a USH1-causing pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a USH1-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has USH1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH1-related gene.
• Assuming that: (1) the prevalence of Usher syndrome is one in 20,000, (2) 30% of individuals with Usher syndrome have type I, and (3) 60% of individuals with USH1 have biallelic pathogenic variants in MYO7A; the population carrier frequency is approximately one in 165 for an MYO7A pathogenic variant. Thus, for each pregnancy of a couple in which one partner has USH1 and the other partner has normal hearing and no family history of Usher syndrome, the probability of a child having Usher syndrome due to biallelic pathogenic variants in MYO7A is approximately one in 330. When similar calculations are done for the other molecular etiologies of USH1, the total probability of this couple having a child with USH1 is approximately one in 300. (Note that this probability would not be correct if both parents are of Acadian or Ashkenazi Jewish ancestry.)

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in a USH1-related gene.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the USH1-causing pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA and/or cellular banking is the storage of DNA (typically extracted from white blood cells) or cells for possible future use in research to improve understanding of Usher syndrome and to develop new therapies. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA and/or cells of affected individuals. For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the USH1-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Usher syndrome is the most frequent genetic cause of concurrent deaf-blindness. It is clinically and genetically heterogeneous. Currently, three clinical types and ten different genes (subtypes) are associated with Usher syndrome. The proteins encoded by the six known Usher syndrome type I (USH1) genes are hypothesized to interact with one another. These proteins are expressed in the eye and ear during and after development, forming a critical macromolecular complex necessary for the development of cilia structure and function. If any one protein in this "Usher interactome" is nonfunctional or absent, sensorineural degeneration occurs in the inner ear and the retina [Bonnet & El-Amraoui 2012, Mathur & Yang 2015, Géléoc & El-Amraoui 2020].

• MYO7A encodes myosin VII (USH1B).
• USH1C encodes are harmonin (USH1C).
• CDH23 encodes cadherin-23 (USH1D).
• PDCH5 encodes protocadherin 15 (USH1F).
• USH1G encodes sans (USH1G).
• CIB2 encodes CIB2 (USH1J).

Note: A comprehensive set of databases (UMD-USHbases) provides information about pathogenic variants responsible for Usher syndrome [Baux et al 2008].

Mechanism of disease causation. Pathogenic variants in USH1 genes result in defects in cochlear hair cell development and photoreceptor maintenance. The autosomal recessive inheritance of USH1 strongly suggests a loss-of-function mechanism.

Acknowledgments

Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital

Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha

Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden

Research supported by FFB and NIH

Author History

Moises A Arriaga, MD, MBA, FACS (2020-present)
Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)
William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)
Robert K Koenekoop, MD, PhD, FACS (2020-present)
Jennifer J Lentz, PhD (2006-present)
Sandra Pieke-Dahl, PhD; Ohio State University (1999-2006)
Karmen M Trzupek, MS, CGC (2020-present)
Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)

Revision History

• 8 October 2020 (jjl) Revision: C-18-04 antioxidant treatment clinical trial now active (Therapies Under Investigation)
• 25 June 2020 (sw) Comprehensive update posted live
• 19 May 2016 (sw) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 28 October 2010 (me) Comprehensive update posted live
• 29 June 2010 (cd) Revision: sequence analysis and prenatal testing available for USH1G; USHIH locus added
• 28 May 2009 (me) Comprehensive update posted live
• 14 May 2008 (cd) Revision: prenatal testing available for CDH23
• 10 December 2007 (cd) Revision: sequence analysis of exon 3 of USH1C available clinically
• 5 November 2007 (cd) Revision: sequence analysis of the entire coding regions of PCDH15 (USH1F) and CDH23 (USH1D) available clinically
• 7 November 2006 (me) Comprehensive update posted live
• 6 February 2004 (cd) Revision: change in gene name (SANS to USH1G)
• 13 January 2004 (wk) Author revisions
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission

Published Guidelines / Consensus Statements

• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 5-30-23.
• American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available online. 2002. Accessed 5-30-23.

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